ClinVar Genomic variation as it relates to human health

In a 3.5-year-old Polish girl with polyuria who was discovered to have nephrocalcinosis and high-normal serum calcium at age 18 months (HCINF2; 616963), Schlingmann et al. (2016) identified homozygosity for a 21-bp deletion (c.271_291del, NM_003052) in exon 4 of the SLC34A1 gene, resulting in the in-frame deletion of 7 amino acids (91del7). The deletion was found in heterozygosity in her unaffected parents, and was also present in the Exome Variant Server with an allele frequency of approximately 2.6% in the European American population; testing of a larger sample yielded an allele frequency of approximately 1.6% (8 of 512 alleles). The deletion was also detected in compound heterozygosity in 3 additional unrelated patients with infantile hypercalcemia: the second allele carried an L155P, W305X, or V408E mutation, respectively, in a 17-year-old Polish boy, a 3-year-old German girl, and a 6-year-old Belgian girl. Functional analysis in Xenopus oocytes showed that wildtype protein induced significant uptake of labeled phosphate, and the 91del7 mutant induced uptake comparable to wildtype. Both missense mutants did not induce uptake that was significantly different from that of noninjected control cells. In transiently transfected opossum kidney cells, the 91del7 mutant was found to be expressed both in intracellular compartments as well as at the plasma membrane, indicating partial retention of this variant inside the cell; however, both missense mutants showed complete intracellular retention of the mutant proteins with no detectable actin colocalization, in contrast to wildtype, which localized at the plasma membrane and colocalized with actin. (less)